Amplification of the Epidermal Growth Factor Receptor gene (EGFR) represents the most common oncogene activation event in glioblastoma, the most common and malignant form of brain tumor. In the vast majority of glioblastomas, EGFR amplification is accompanied by EGFR mutation. Little is known, however, about the functional and biologic consequences of the mutations that have been identified. Understanding these consequences is important because many of the therapies that are under consideration for the treatment of cancer patients rely upon the effects of chemical inhibitors intended to block the function of receptor tyrosine kinases (RTKs) such as EGFR, or the signaling proteins downstream of RTKs. The investigators propose to initiate a systematic functional and biologic analysis of mutant Egf receptors known to be expressed in human glioblastomas. This analysis will be accompanied by studies examining the effects of chemical inhibitors on wild type and mutant Egf receptor signaling, and will additionally include an investigation of the evolution of EGFR amplification/mutation in vitro as well as in vivo. In total, it is anticipated that the information obtained through the implementation of this project will lead to the identification of conditions that select for the expression of Egf receptor mutants, and an improved understanding of the functional and biologic consequences of this selective process.